Taxoids macrocyclic

Metaferia et al. reported on the synthesis and cytotoxicity of C3 -C4 linked macrocyclic taxoids in 2001. The synthetic strategy was also based on RCM. Similar to Ojima et al. s finding, these compounds (100) are less active than paclitaxel in both cytotoxicity and tubulin assays.However, after careful inspection of the bioactive conformations of taxoids with computer simulation and nuclear magnetic resonance (NMR) experiments, they designed several C-4 and C3 -Ph orf/io-position linked taxoids (101) that were highly active, several times better than paclitaxel. ... 

Some macrocyclic taxoids such as 99b and 99c were among the most potent inhibitors for dmg-resistant cancer cells. 

Ojima, I. Geng, X. Lin, S. Pera, R Bemacki, R. Design, synthesis and biological activity of novel C2-C3 N-linked macrocyclic taxoids. Bioorg. Med. Chem. Lett., 2002, 12 349-352. 

Querolle, O. Dubois, J. Thoret, S. Dupont, C. Gueritte, R Guenard, D. Synthesis of novel C-2,C3 -N linked macrocyclic taxoids with variable ring size. Eur. J. Org. Chem., 2003, 542-550. 

Sun, L., Geng, X., Geney, R., et al. (2008) Design, synthesis and biological evaluation of novel C14-C3 BzN-linked macrocyclic taxoids, Journal of Organic Chemistry, 73, 9584-9593. 

Ojima I, Lin S, Inoue T, Miller ML, Borella CP, Geng X, Walsh JJ (2000) Macrocycle Formation by Ring-Closing Metathesis. Application to the Syntheses of Novel Macrocyclic Taxoids. J Am Chem Soc 122 5343... 

Regioselective Mizoroki-Heck macrocyclization was also a key step in the synthesis of macrocyclic taxoids. Ojima and coworkers [162] prepared macrocyclic taxoid 220 under very mild standard Mizoroki-Heck conditions in an excellent yield of 87% over two steps (Scheme 6.67). 

Scheme 6.67 High-yielding synthesis of macrocyclic taxoid 220.

Geng, X., Miller, M.L., Lin, S. and Ojima, 1. (2003) Synthesis of novel C2—C3 N-linked macrocyclic taxoids by means of highly regioselective Heck macrocyclization. Org. Lett., 5, 3733-6. 

In an illustration of the degree of functionality and structural complexity this reaction can accept, a number of macrocyclic taxoid derivatives (46, Figure 11.6, site of cyclization indicated along with the catalyst employed using the designations in Figure 11.5) were synthesized using RCM and assisted in the determination of the active conformation of this class of anticancer natural products. 

As another instance of a ruthenium-catalysed process, a macrocyclic taxoid, SB-T-2054 (134), was prepared from an unexpected diene-coupling reaction... 

Novel macrocyclic and open-chain taxoid mimicking compounds were synthesized. Two of these, compounds 283 and 284, were found to possess cytotoxicity with micromolar level IC50 values against human breast cancer cell lines <2004BML3491>. 

Epothilones, isolated from the mycobacterium Sorangium cellulosum in 1996, are a new class of cytotoxic macrolides that are especially effective against drug-resistant tumor cell lines by the same mechanism as the taxoids. The structural feature of epothilones (Fig. 1) includes a 16-membered lactone ring, p-hydroxyl carbonyl units and cw-epoxide on the macrocyclic ring, and a thiazole unit as the side chain. 

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